Temporal lobe epilepsy is common and difficult to treat. Our long-range research goal is to help reveal mechanisms of temporal lobe epilepsy and develop anti-epileptogenic strategies. During the last funding period we discovered rapamycin suppresses granule cell axon (mossy fiber) sprouting and found that despite substantial reductions, spontaneous seizure frequency was unchanged in a mouse model of temporal lobe epilepsy. These findings raise doubts about the role of mossy fiber sprouting in epileptogenesis. However, scattered clues in the literature and preliminary findings suggest another recurrent, excitatory circuit in the dentate gyrus developed despite suppression of mossy fiber sprouting. The goal of the next funding period is to test the hypothesis that in a rat model of temporal lobe epilepsy surviving mossy cells function as aberrant network hubs, establish an over-developed positive-feedback circuit within the dentate gyrus, and contribute to the generation of spontaneous seizures. We propose 3 specific aims.
Aim 1 is to test the hypothesis that surviving mossy cells enlarge, elongate dendritic processes, and receive more excitatory synaptic input in epileptic pilocarpine-treated rats. Hippocampal slices, whole-cell patch recording, and biocytin labeling will be used.
Aim 2 is to test the hypothesis that surviving mossy cells sprout axon collaterals and form new synapses with granule cells in epileptic pilocarpine-treated rats. In vivo intracellular biocytin-labeling and electron microscopy will be used.
Aim 3 is to perform 3 experiments to test the hypothesis that surviving mossy cells contribute to seizure generation. Unit recordings will be obtained from mossy cells in epileptic pilocarpine- treated rats as they experience spontaneous seizures. Seizure frequency and numbers of surviving mossy cells will be measured to determine whether there is a correlation. And, we will test whether epilepsy-related changes in mossy cell circuitry are resistant to rapamycin treatment. Achieving these aims will clarify the role of surviving hilar mossy cells in temporal lobe epilepsy. If mossy cells do play an epileptogenic role, then they may offer new therapeutic targets to dampen excitability and provide better seizure control for patients.

Public Health Relevance

Many patients with epilepsy have uncontrolled spontaneous seizures that initiate in or near hippocampal dentate gyrus. Seizures might be caused by aberrant positive-feedback circuits that develop after epilepsy- causing injuries. This project will test whether a specific abnormal circuit develops in the dentate gyrus and contributes to the generation of spontaneous seizures.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040276-12
Application #
8286800
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Whittemore, Vicky R
Project Start
2000-07-05
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
12
Fiscal Year
2012
Total Cost
$344,998
Indirect Cost
$130,623
Name
Stanford University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Yamawaki, Ruth; Thind, Khushdev; Buckmaster, Paul S (2015) Blockade of excitatory synaptogenesis with proximal dendrites of dentate granule cells following rapamycin treatment in a mouse model of temporal lobe epilepsy. J Comp Neurol 523:281-97
Zhang, Wei; Thamattoor, Ajoy K; LeRoy, Christopher et al. (2015) Surviving mossy cells enlarge and receive more excitatory synaptic input in a mouse model of temporal lobe epilepsy. Hippocampus 25:594-604
Buckmaster, Paul S (2014) Does mossy fiber sprouting give rise to the epileptic state? Adv Exp Med Biol 813:161-8
Heng, Kathleen; Haney, Megan M; Buckmaster, Paul S (2013) High-dose rapamycin blocks mossy fiber sprouting but not seizures in a mouse model of temporal lobe epilepsy. Epilepsia 54:1535-41
Buckmaster, Paul S; Wen, Xiling (2011) Rapamycin suppresses axon sprouting by somatostatin interneurons in a mouse model of temporal lobe epilepsy. Epilepsia 52:2057-64
Buckmaster, Paul S; Lew, Felicia H (2011) Rapamycin suppresses mossy fiber sprouting but not seizure frequency in a mouse model of temporal lobe epilepsy. J Neurosci 31:2337-47
Lyons, David M; Buckmaster, Paul S; Lee, Alex G et al. (2010) Stress coping stimulates hippocampal neurogenesis in adult monkeys. Proc Natl Acad Sci U S A 107:14823-7
Ingram, Elizabeth A; Toyoda, Izumi; Wen, Xiling et al. (2009) Prolonged infusion of inhibitors of calcineurin or L-type calcium channels does not block mossy fiber sprouting in a model of temporal lobe epilepsy. Epilepsia 50:56-64
Zhang, Wei; Buckmaster, Paul S (2009) Dysfunction of the dentate basket cell circuit in a rat model of temporal lobe epilepsy. J Neurosci 29:7846-56
Buckmaster, Paul S; Ingram, Elizabeth A; Wen, Xiling (2009) Inhibition of the mammalian target of rapamycin signaling pathway suppresses dentate granule cell axon sprouting in a rodent model of temporal lobe epilepsy. J Neurosci 29:8259-69

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